rs17091705

Positions:

• chr20-34285641-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000687.4(AHCY):​c.973-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 1,612,020 control chromosomes in the GnomAD database, including 5,500 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2864 hom., cov: 32)
  • Exomes 𝑓: 0.011 (2636 hom.)
• Consequence: AHCY NM_000687.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002591
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.36

Genes affected

AHCY (HGNC:343): (adenosylhomocysteinase) S-adenosylhomocysteine hydrolase belongs to the adenosylhomocysteinase family. It catalyzes the reversible hydrolysis of S-adenosylhomocysteine (AdoHcy) to adenosine (Ado) and L-homocysteine (Hcy). Thus, it regulates the intracellular S-adenosylhomocysteine (SAH) concentration thought to be important for transmethylation reactions. Deficiency in this protein is one of the different causes of hypermethioninemia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2009]

AHCY (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 20-34285641-G-A is Benign according to our data. Variant chr20-34285641-G-A is described in ClinVar as [Benign]. Clinvar id is 338270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHCY	NM_000687.4	c.973-7C>T		splice_region_variant, intron_variant		ENST00000217426.7	NP_000678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AHCY	ENST00000217426.7	c.973-7C>T		splice_region_variant, intron_variant		1	NM_000687.4	ENSP00000217426.2
AHCY	ENST00000538132.1	c.889-7C>T		splice_region_variant, intron_variant		2		ENSP00000442820.1
AHCY	ENST00000480653.5	n.1121-7C>T		splice_region_variant, intron_variant		2
ENSG00000272945	ENST00000609218.1	n.439+387C>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16073 AN: 151944 Hom.: 2863 Cov.: 32

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0476

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000971

Gnomad OTH AF: 0.0723

GnomAD3 exomes AF: 0.0273 AC: 6767 AN: 248266 Hom.: 1129 AF XY: 0.0204 AC XY: 2750 AN XY: 134662

Gnomad AFR exome AF: 0.371

Gnomad AMR exome AF: 0.0170

Gnomad ASJ exome AF: 0.00229

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.000948

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000568

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0108 AC: 15777 AN: 1459958 Hom.: 2636 Cov.: 31 AF XY: 0.00931 AC XY: 6766 AN XY: 726374

Gnomad4 AFR exome AF: 0.379

Gnomad4 AMR exome AF: 0.0208

Gnomad4 ASJ exome AF: 0.00210

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000402

Gnomad4 OTH exome AF: 0.0247

GnomAD4 genome AF: 0.106 AC: 16087 AN: 152062 Hom.: 2864 Cov.: 32 AF XY: 0.102 AC XY: 7594 AN XY: 74360

Gnomad4 AFR AF: 0.365

Gnomad4 AMR AF: 0.0475

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000971

Gnomad4 OTH AF: 0.0716

Alfa AF: 0.0181 Hom.: 794

Bravo AF: 0.121

Asia WGS AF: 0.0160 AC: 58 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2020	- -

Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.1
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17091705; hg19: chr20-32873447;